Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models

Abstract

Resistance to targeted EGFR inhibitors is likely to develop in EGFR mutant lung cancers. Early identification of innate or acquired resistance mechanisms to these agents is essential to direct development of future therapies. We describe the detection of heterogeneous mechanisms of resistance within populations of EGFR mutant cells (PC9 and/or NCI-H1975) with acquired resistance to current and newly developed EGFR TKIs including AZD9291. We report the detection of NRAS mutations, including a novel E63K mutation, and a gain of copy number of WT NRAS or WT KRAS in cell populations resistant to gefitinib, afatinib, WZ4002 or AZD9291. Compared to parental cells, a number of resistant cell populations were more sensitive to inhibition by the MEK inhibitor selumetinib (AZD6244; ARRY-142886) when treated in combination with the originating EGFR inhibitor. In vitro, a combination of AZD9291 with selumetinib prevented emergence of resistance in PC9 cells and delayed resistance in NCI-H1975 cells. In vivo, concomitant dosing of AZD9291 with selumetinib caused regression of AZD9291-resistant tumours in an EGFRm/T790M transgenic model. Our data support the use of a combination of AZD9291 with a MEK inhibitor to delay or prevent resistance to AZD9291 in EGFRm and/or EGFRm/T790M tumours. Further, these findings suggest that NRAS modifications in tumour samples from patients who have progressed on current or EGFR inhibitors in development may support subsequent treatment with a combination of EGFR and MEK inhibition.

Optimizing outcomes in EGFR Mutation-Positive Nsclc: Which Tyrosine Kinase Inhibitor and When?

“…Preclinical studies have also identified potential resistance mechanisms. For example, cells that are resistant to osimertinib appear to have enhanced levels of phosphorylated MEK and may be particularly sensitive to combined EGFR and MEK inhibition [57,58]. The identification of heterogeneous resistance mechanisms to osimertinib has prompted the initiation of several early-phase clinical trials [59].…”

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

“…Eberlein and colleagues conducted a very meaningful pre-clinical study regarding the involvement of RAS-MAPK pathway in acquired resistance to third-generation TKIs (31). With a comparison across 32 populations of cell lines with acquired resistance to different EGFR-TKIs, the authors detected, as frequent mechanisms of resistance to osimertinib, NRAS missense mutations (including a novel E63K mutation) or NRAS copy number gain.…”

Tyrosine kinase inhibitors: new molecules in non-small cell lung cancer (EGFR AND ALK)

“…AZ7550 showed a comparable potency and selectivity profile similar to osimertinib, whereas AZ5104 in addition exhibited greater potency against exon 19 deletion and T790M mutants and wild-type EGFR. The first phase I dose escalation study was the AURA, made with EGFR mutated patients in progression with gefitinib or erlotinib treatment [11,[16][17][18]. The doses used were between 20 and 240 mg per day.…”

“…The most frequent were rash, diarrhea and nausea. Since no significant difference in response to higher doses was observed, 80 mg/day is recommended until disease progression or unacceptable toxicity [16][17][18]. If it is necessary to reduce the dose, this should be done at 40 mg per day, since tablets are 40 and 80 mg. Its elimination is mainly hepatic and has not been studied in patients with renal insufficiency [16].…”